The present invention relates to novel substituted bicyclic derivatives that are dopamine receptor subtype ligands having a preference for the D4-dopamine receptor. These compounds exhibit central dopaminergic activity, as defined below, and are useful in the treatment and prevention of disorders of the dopamine system, including schizophrenic and schizo-affective disorders, akinesia, dementia, Parkinson""s disease, nausea, bipolar disorders, emesis, tardive dyskinesia, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, hyperprolactemia and amenorrhoea.
It is known that dopamine receptors are important for many functions in mammals. For example, altered functions of these receptors are thought to participate in the genesis of psychosis, drug addiction, compulsive disorders, bipolar disorders, vision, emesis, sleep, feeding, learning, memory, sexual behavior, regulation of immunological responses and blood pressure.
This invention relates to compounds of the formula 1 
and to pharmaceutically acceptable salts and solvates thereof wherein:
each dashed line in the above formula represents an optional double bond, provided that both dashed lines do not simultaneously represent a double bond;
X1 and X2 are each independently selected from O and xe2x80x94(CH2)jxe2x80x94 wherein j is 1 or 2, provided that no O is doubly-bonded to an adjacent atom;
X3 is xe2x80x94CH(R5)N(R8)CH(R6)xe2x80x94, xe2x80x94CH(R5)C(R8)(R9)CH(R6)xe2x80x94, xe2x80x94C(R5)xe2x95x90C(R8)CH(R6)xe2x80x94, or xe2x80x94CH(R5)C(R8)xe2x95x90C(R6)xe2x80x94;
R1 and R2 are each independently H, hydroxy, or C1-C6 alkyl;
or R1 and R2 are taken together as a bond;
each R3 is independently selected from xe2x80x94S(O)jR7 wherein j is an integer ranging from 0 to 2, xe2x80x94C(O)R7, xe2x80x94OR7, xe2x80x94NC(O)R7, xe2x80x94NR7R12, and the substituents provided in the definition of R other than H;
R4 is absent where the dashed line in the above formula 1 represents a double bond or R4 is selected from H and the substituents provided in the definition of R3;
or R3 and R4 are taken together with the carbon atom to which each is attached to form a 5-10 membered mono-cyclic or bicyclic group wherein said cyclic group may be carbocyclic or heterocyclic with 1 to 3 heteroatoms selected from O, S, and xe2x80x94N(R11)xe2x80x94 with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said cyclic group is saturated or partially unsaturated; aromatic or non-aromatic; 1 or 2 of the carbon atoms in said cyclic group optionally may be replaced by an oxo xe2x80x94C(O)xe2x80x94 moiety; and said cyclic group is optionally substituted by 1 to 3 R10 groups;
R5 and R6 are each independently selected from H and C1-C4 alkyl;
or R5 and R6 are taken together as xe2x80x94(CH2)qxe2x80x94 wherein q is 2 or 3;
or R5 or R6 is taken together with R8 as defined below;
each R7 is independently selected from H, xe2x80x94(CH2)t(C6-C10 aryl) and xe2x80x94(CH2)t(4-10 membered heterocyclic), wherein t is an integer ranging from 0 to 5; 1 or 2 of the carbon atoms of said heterocyclic group optionally may be replaced with an oxo xe2x80x94C(O)xe2x80x94 group; said aryl and heterocyclic R7 groups are optionally fused to a benzene ring, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; the xe2x80x94(CH2)txe2x80x94 moieties of the foregoing R7 groups optionally include a carbonxe2x80x94carbon double or triple bond where t is an integer between 2 and 5; and the foregoing R7 groups, except H, are optionally substituted by 1 to 5 R10 groups;
R8 is selected from the substituents provided in the definition of R7 other than H;
R9 is selected from the substituents provided in the definition of R7;
or R8 and R9 are taken together with the carbon to which each is attached to form a 5-10 membered mono-cyclic or bicyclic group wherein said cyclic group is carbocyclic or heterocyclic with 1 to 3 heteroatoms selected from O, S, and xe2x80x94N(R11)xe2x80x94 with the proviso that two O atoms, two S atoms, or an 0 and S atom are not attached directly to each other; saturated or partially unsaturated; aromatic or non-aromatic; 1 or 2 of the carbon atoms in said cyclic group optionally may be replaced by an oxo xe2x80x94C(O)xe2x80x94 moiety; and said cyclic group is optionally substituted by 1 to 3 R10 groups;
or R8 taken together with either R5 or R6 and the separate carbon atoms to which each is attached to form a fused 5-10 membered mono-cyclic or bicyclic group wherein said cyclic group may be carbocyclic or heterocyclic with 1 to 3 heteroatoms selected from O, S, and xe2x80x94N(R11)xe2x80x94 with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; saturated or partially unsaturated; aromatic or non-aromatic; 1 or 2 of the carbon atoms in said cyclic group optionally may be replaced by an oxo xe2x80x94C(O)xe2x80x94 moiety; and said cyclic group is optionally substituted by 1 to 3 R10 groups;
each R10 is independently selected from C1-C10 alkyl, C2-C10, alkenyl, C2-C10 alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94OR11, xe2x80x94C(O)R11, xe2x80x94C(O)OR11, xe2x80x94NR12C(O)OR11, xe2x80x94OC(O)R11, xe2x80x94NR12SO2R11, xe2x80x94SO2NR11R12, xe2x80x94NR12C(O)R11, xe2x80x94C(O)NR11R12, xe2x80x94NR11R12, xe2x80x94S(O)j(C1-C6 alkyl) wherein j is an integer ranging from 0 to 2, xe2x80x94(CH2)m(C6-C10 aryl), xe2x80x94SO2(CH2)j(C6-C10 aryl), xe2x80x94S(CH2)m(C6-C10 aryl), xe2x80x94O(CH2)m(C6-C10 aryl) and xe2x80x94(CH2)m(4-10 membered heterocyclic), wherein m is an integer ranging from 0 to 4; said C1-C10 alkyl group optionally contains 1 or 2 hetero moieties selected from O, S and xe2x80x94N(R12)xe2x80x94 with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic R10 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, aryl and heterocyclic R10 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94NR12SO2R11, xe2x80x94SO2NR11R12, xe2x80x94C(O)R11, xe2x80x94C(O)OR11, xe2x80x94OC(O)R11, xe2x80x94NR12C(O)R11, xe2x80x94C(O)NR11R12, xe2x80x94NR11R12, C1-C6 alkyl, xe2x80x94OR11 and the substituents listed in the definition of R11;
each R11 is independently selected from H, C1-C10 alkyl, xe2x80x94(CH2)m(C6-C10 aryl), and xe2x80x94(CH2)m(4-10 membered heterocyclic), wherein m is an integer ranging from 0 to 4; said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and xe2x80x94N(R12)xe2x80x94 with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic R11 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R11 substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94CO(O)R12, xe2x80x94NR12C(O)R13, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy; and,
each R12 and R13 is independently H or C1-C6 alkyl.
In an emobdiment of the invention, compounds of the invention of formula 1 have the following structure 
wherein R1, R2, R3, R4, X1, X2, and X3 are as defined above.
Other embodiments of the compounds of formula 1 include those wherein formula 1 has the following structure 
wherein R3 is xe2x80x94(CH2)t(C6-C10 aryl) or xe2x80x94(CH2)t(4-10 membered heterocyclic), R4 is H or hydroxy, and R1 is xe2x80x94(CH2)t(C6-C10 aryl) or xe2x80x94(CH2)t(4-10 membered heterocyclic), t is an integer ranging from 0 to 5, and the foregoing R3 and R8 heterocyclic groups are optionally fused to a 5 benzene ring, and said R3 and R8 groups are optionally substituted by 1 to 3 R10 groups. More specific embodiments include those wherein R8 and R3 are each independently selected from phenyl and pyrimidyl, optionally substituted by 1 to 3 substituents independently selected from halo, cyano, methoxy, trifluoromethyl, methanesulfonyl, amino, trifluoromethoxy, acetamido, and C1-C6 alkyl. Other more specific embodiments include those wherein R3 is a heterocyclic group fused to a benzene ring and, optionally, 1 or 2 of the carbon atoms of said heterocyclic group is replaced with an oxo xe2x80x94C(O)xe2x80x94 group. In particular, such specific embodiments of R3 include the following groups: 
wherein the benzo portion of the above R3 groups is optionally substituted by 1 to 3 R10 groups.
Other embodiments of the compounds of formula 1 include those wherein formula 1 has the following structure 
wherein R3 is xe2x80x94O(CH2)t(C6-C10 aryl) or xe2x80x94O(CH2)t(4-10 membered heterocyclic), R4 is H or hydroxy, and R8 is xe2x80x94(CH2)t(C6-C10 aryl) or xe2x80x94(CH2)t(4-10 membered heterocyclic), wherein t is an integer ranging from 0 to 5, and wherein the foregoing R3 and R8 groups are optionally substituted by 1 to 3 R10 groups. More specific embodiments include those wherein R3 is phenoxy and R8 is phenyl or pyrimidyl, and said R3 and R1 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, methoxy, trifluoromethyl, methanesulfonyl, amino, trifluoromethoxy, acetamido, and C1-C6 alkyl.
Other embodiments of the compounds of formula 1 include those wherein formula 1 has the following structure 
wherein R3 and R4 are taken together with the carbon atom to which each is attached to form a 5-10 membered mono-cyclic or bicyclic group wherein said cyclic group may be carbocyclic or heterocyclic with 1 to 3 heteroatoms selected from O, S, and xe2x80x94N(R11)xe2x80x94 with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said cyclic group is saturated or partially unsaturated; aromatic or non-aromatic; 1 or 2 of the carbon atoms in said cyclic group optionally may be replaced by an oxo xe2x80x94C(O)xe2x80x94 moiety;
and said cyclic group is optionally substituted by 1 to 3 R10 groups; and R8 is xe2x80x94(CH2)t(C6-C10 aryl) or xe2x80x94(CH2)t(4-10 membered heterocyclic), wherein t is an integer ranging from 0 to 5 and said R8 group is optionally substituted by 1 to 3 R10 groups. More specific embodiments include those wherein R8 is phenyl or pyrimidyl, and R3 and R4 are taken together to form a group selected from 
and said R8, R3 and R4 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, methoxy, trifluoromethyl, methanesulfonyl, amino, trifluoromethoxy, acetamido, and C1-C6 alkyl.
Specific embodiments of the compounds of formula 1 include those selected from
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5xe2x80x2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-hexahydropentalene-2xe2x80x2-one;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5xe2x80x2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2xe2x80x2-phenyl-octahydro-pentalen-2xe2x80x2ol, maleate salt;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5xe2x80x2-[4-(4-Cyano-3-fluoro-phenyl)-piperazin-1-yl]-hexahydropentalene-2-one, ethylene ketal;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5xe2x80x2-[4-(4-Cyano-3-fluoro-phenyl)-piperazin-1-yl]-hexahydropentalene-2-one;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-[4-(5xe2x80x2-hydroxy-5xe2x80x2-phenyl-octahydro-pentalen-2xe2x80x2-yl)-pipeerazin-1-yl]-benzonitrile, maleate salt;
(2xcex1,3axcex2,5xcex1,6axcex2)-5-Hydroxy-5-phenyl-hexahydro-pentalen-2-one;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xcex1,6xe2x80x2axcex2)-5xe2x80x2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-2xe2x80x2-phenyl-octahydro-pentalen-2xe2x80x2ol, maleate salt;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5xe2x80x2-[4-(4-Fluoro-1-pyrimidyl)-piperazin-1-yl]-2xe2x80x2-(4-fluoro-phenyl)-octahydro-pentalen-2xe2x80x2ol, maleate salt;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5xe2x80x2-[4-(4-Cyano-3-fluoro-phenyl)-piperazin-1-yl]-2xe2x80x2-(4-fluoro-phenyl)-octahydro-pentalen-2xe2x80x2ol, maleate salt;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5xe2x80x2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2xe2x80x2-(4-fluoro-phenyl)-octahydro-pentalen-2xe2x80x2ol, maleate salt;
(2xe2x80x2xcex1,3xe2x80x2axcex2,6xe2x80x2axcex2)-1-(4-Fluoro-phenyl)-4-(5xe2x80x2-phenyl-1xe2x80x2,2xe2x80x2,3xe2x80x2,3xe2x80x2a,4xe2x80x2,6xe2x80x2a-hexahydro-pentalen-2xe2x80x2-yl)-piperazine dihydrochloride;
(2xe2x80x2xcex1,3xe2x80x2axcex2,6xe2x80x2axcex2)-5-Fluoro-2-[4-(5xe2x80x2-phenyl-1xe2x80x2,2xe2x80x2,3xe2x80x2,3xe2x80x2a,4xe2x80x2,6xe2x80x2a-hexahydro-pentalen-2xe2x80x2-yl)-piperazin-1-yl]-pyrimidine maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,6xe2x80x2a xcex2)-2-Fluoro-4-[4-(5xe2x80x2-phenyl-1xe2x80x2,2xe2x80x2,3xe2x80x2,3xe2x80x2a,4xe2x80x2,6xe2x80x2a-hexahydro-pentalen-2xe2x80x2-yl)-piperazin-1-yl]-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,6xe2x80x2axcex2)-2-Fluoro-4-{4-[5-(2-methoxy-phenyl)-1xe2x80x2,2xe2x80x2,3xe2x80x2,3xe2x80x2a,4xe2x80x2,6xe2x80x2a-hexahydro-pentalen-2xe2x80x2-yl]-piperazin-1-yl}-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,6xe2x80x2axcex2)-1-Phenyl-4-(5xe2x80x2-phenyl-1xe2x80x2,2xe2x80x2,3xe2x80x2,3xe2x80x2a,4xe2x80x2,6xe2x80x2a-hexahydro-pentalen-2xe2x80x2-yl)-piperazine, dimaleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-1-(4-Fluoro-phenyl)-4-(5xe2x80x2-phenyl-octahydro-pentalen-2xe2x80x2-yl)-piperazine, dihydrochloride;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5-Fluoro-2-[4-(5xe2x80x2-phenyl-octahydro-pentalen-2xe2x80x2-yl)-piperazin-1-yl]-pyrimidine, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-[4-(5xe2x80x2-phenyl-octahydro-pentalen-2xe2x80x2-yl)-piperazin-1-yl]-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-1-Phenyl-4-(5xe2x80x2-phenyl-octahydro-pentalen-2xe2x80x2-yl)-piperazine, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5xe2x80x2-Hydroxy-5xe2x80x2-(2-trifluoromethyl-phenyl)-hexahydro-pentalen-2xe2x80x2-one;
(2xe2x80x2xcex1,3xe2x80x2axcex2,6xe2x80x2axcex2)-5xe2x80x2-(2-trifluoromethyl-phenyl)-3,3a,4,6a-tetrahydro-1H-pentalen-2xe2x80x2-one, ethylene ketal;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5xe2x80x2-(2-Trifluoromethyl-phenyl)-hexahydro-1H-pentalen-2xe2x80x2-one, ethylene ketal;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5xe2x80x2-(2-Trifluoromethyl-phenyl)-hexahydro-1H-pentalen-2xe2x80x2-one;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-{4-[5xe2x80x2-(2-trifluoromethyl-phenyl)-octahydro-pentalen-2xe2x80x2-yl]-piperazin-1-yl}-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-{4-[5xe2x80x2-(2-methoxy-phenyl)-octahydro-pentalen-2xe2x80x2-yl]-piperazin-1-yl}-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5-Fluoro-2-{4-[5xe2x80x2-(2-methoxy-phenyl)-octahydro-pentalen-2xe2x80x2-yl]-piperazin-1-yl}-pyrimidine, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-{4-[5xe2x80x2-(3-methoxy-phenyl)-octahydro-pentalen-2xe2x80x2-yl]-piperazin-1-yl}-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-{4-[5xe2x80x2-(4-methoxy-phenyl)-octahydro-pentalen-2xe2x80x2-yl]-piperazin-1-yl}-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-[4-(5xe2x80x2-o-tolyl-octahydro-pentalen-2xe2x80x2-yl)-piperazin-1-yl]-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5-Fluoro-2-[4-(5xe2x80x2-o-tolyl-octahydro-pentalen-2xe2x80x2-yl)-piperazin-1-yl]-pyrimidine, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5-Chloro-2-{4-[5xe2x80x2-(2-methoxy-phenyl)-octahydro-pentalen-2xe2x80x2-yl]-piperazin-1-yl}-pyrimidine, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5-Chloro-2-[4-(5xe2x80x2-o-tolyl-octahydro-pentalen-2xe2x80x2-yl)-piperazin-1-yl]-pyrimidine, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-{4-[5xe2x80x2-(2-methanesulfonyl-phenyl)-octahydro-pentalen-2xe2x80x2-yl]-piperazin-1-yl}-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-1-Phenyl-4-[5xe2x80x2-(3-pyrrolidin-1-ylmethyl-phenyl)-octahydro-pentalen-2xe2x80x2-yl]-piperazine, dimaleate;
5-Trimethylstannayl-3,3a,4,6a-tetrahydro-1H-pentalen-2-one, ethylene ketal;
5-(2-Cyano-phenyl)-3,3a,4,6a-tetrahydro-1H-pentalen-2-one;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Cyano-4-{4-[5xe2x80x2-(2-fluoro-phenyl)-octahydro-pentalen-2xe2x80x2-yl]-piperazin-1-yl}-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-{4-[5xe2x80x2-(2-trifluoromethoxy-phenyl)-octahydro-pentalen-2xe2x80x2-yl]-piperazin-1-yl}-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-{4-[5xe2x80x2-(2-fluoro-phenyl)-octahydro-pentalen-2xe2x80x2-yl]-piperazin-1-yl}-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-[4-(5xe2x80x2-pyridin-2-yl-octahydro-pentalen-2xe2x80x2-yl)-piperazin-1-yl]-benzonitrile, dihydrochloride;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-[4-(5xe2x80x2-m-tolyl-octahydro-pentalen-2xe2x80x2-yl)-piperazin-1-yl]-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-[4-(5xe2x80x2-p-tolyl-octahydro-pentalen-2xe2x80x2-yl)-piperazin-1-yl]-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-N-(2-{5xe2x80x2-[4-(5-Fluoro-pyrimidin-2-yl)-piperazin-1-yl]-octahydro-pentalen-2xe2x80x2-yl}-phenyl)-acetamide, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-N-(2-{5xe2x80x2-[4-(4-Cyano-3-fluoro-phenyl)-piperazin-1yl]-octahydro-pentalen-2xe2x80x2-yl}-phenyl)-acetamide, maleate;
5-(2-Cyano-phenyl)-3,3a,4,6a-tetrahydro-1H-pentalen-2-one, ethylene ketal;
2-(5-Oxo-octahydro-pentalen-2-yl)-benzamide, ethylene ketal;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-{5xe2x80x2-[4-(4-Cyano-3-fluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2xe2x80x2-yl}-benzamide, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-[4-(3xe2x80x2,3xe2x80x2a,4xe2x80x2,5xe2x80x2,6xe2x80x2,6xe2x80x2a-hexahydrospiro[isobenzofuran-1(3H), 2xe2x80x2(1xe2x80x2H)-pentalen]-5xe2x80x2-yl)-1-piperazinyl]-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex2,6xe2x80x2axcex2)-2-Fluoro-4-[4-(3xe2x80x2,3xe2x80x2a,4xe2x80x2,5xe2x80x2,6xe2x80x2,6xe2x80x2a-hexahydrospiro[isobenzofuran-1(3H), 2xe2x80x2(1xe2x80x2H)-pentalen]-5xe2x80x2-yl)-1-piperazinyl]-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5-Fluoro-2-[4-(3xe2x80x2,3xe2x80x2a,4xe2x80x2,5xe2x80x2,6xe2x80x2,6xe2x80x2a-hexahydrospiro[isobenzofuran-1(3H), 2xe2x80x2(1xe2x80x2H)-pentalen]-5xe2x80x2-yl)-piperazin-1-yl]-pyrimidine;
(2xe2x80x2xcex2,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5-Fluoro-2-[4-(3xe2x80x2,3xe2x80x2a,4xe2x80x2,5xe2x80x2,6xe2x80x2, 6xe2x80x2a-hexahydrospiro[isobenzofuran-1(3H), 2xe2x80x2(1xe2x80x2H)-pentalen]-5xe2x80x2-yl)-piperazin-1-yl]-pyrimidine;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5-Fluoro-2-[4-(3xe2x80x2, 3xe2x80x2a,4xe2x80x2,5xe2x80x2,6xe2x80x2,6xe2x80x2a-hexahydro-3xe2x80x2a,6xe2x80x2a-dimethylspiro[isobenzofuran-1(3H), 2xe2x80x2(1xe2x80x2H)-pentalen]-5xe2x80x2-yl)-1-piperazinyl]-pyrimidine, maleate;
(2xe2x80x2xcex2,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5-Fluoro-2-[4-(3xe2x80x2,3xe2x80x2a,4xe2x80x2,5xe2x80x2,6xe2x80x2,6xe2x80x2a-hexahydro-3xe2x80x2a,6xe2x80x2a-dimethylspiro[isobenzofuran-1(3H), 2xe2x80x2(1xe2x80x2H)-pentalen]-5xe2x80x2-yl)-1-piperazinyl]-pyrimidine, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-[4-(3,3xe2x80x2,3xe2x80x2a,4,4xe2x80x2,5xe2x80x2,6xe2x80x2,6xe2x80x2a-hexahydrospiro[2H-1-benzopyran-2,2xe2x80x2(1xe2x80x2H)-pentalen]-5xe2x80x2-yl)-1-piperazinyl]-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-[4-(3,3xe2x80x2,3xe2x80x2a,4,4xe2x80x2,5xe2x80x2,6xe2x80x2,6xe2x80x2a-hexahydrospiro[2H-1-benzopyran-2,2xe2x80x2(1xe2x80x2H)-pentalen]-5xe2x80x2-yl)-1-piperazinyl]-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-1-Phenyl-4-(3,3xe2x80x2,3xe2x80x2a,4,4xe2x80x2,5xe2x80x2,6xe2x80x2,6xe2x80x2a-hexahydrospiro[2H-1-benzopyran-2,2xe2x80x2(1xe2x80x2H)-pentalen]-5xe2x80x2-yl]-5xe2x80x2-yl)-piperazine, maleate;
(2xe2x80x2xcex2,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-1-Phenyl-4-(3,3xe2x80x2,3xe2x80x2a,4,4xe2x80x2,5xe2x80x2,6xe2x80x2,6xe2x80x2a-hexahydrospiro[2H-1-benzopyran-2,2xe2x80x2(1xe2x80x2H)-pentalen]-5xe2x80x2-yl]-5xe2x80x2-yl)-piperazine, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-[4-(3,3xe2x80x2,3xe2x80x2a,4,4xe2x80x2,5xe2x80x2,6xe2x80x2,6xe2x80x2a-hexahydrospiro[2H-6-fluoro-1-benzopyran-2,2xe2x80x2(1xe2x80x2H)-pentalen]-5xe2x80x2-yl]-5xe2x80x2-yl)-1-piperazinyl]-benzonitrile, maleate;
(2xe2x80x2xcex2,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-[4-(3,3xe2x80x2,3xe2x80x2a,4,4xe2x80x2,5xe2x80x2,6xe2x80x2,6xe2x80x2a-hexahydrospiro[2H-6-fluoro-1-benzopyran-2,2xe2x80x2(1xe2x80x2H)-pentalen]-5xe2x80x2-yl]-5xe2x80x2-yl)-1-piperazinyl]-benzonitrile, maleate;
(2xcex1,3axcex2,5xcex1,6axcex2)-5-Benzylamino-hexahydropentalen-2-one, mono -ethylene ketal;
(2xcex1,3axcex2,5xcex1,6axcex2)-5-Amino-hexahydropentalen-2-one, mono -ethylene ketal;
(2xcex1, 3axcex2,5xcex1,6axcex2)-5-(5-Fluoro-2-nitro-phenylamino)-hexahydropentalen-2-one, mono-ethylene ketal;
(2xcex1,3axcex2,5xcex1,6axcex2)-5-(2-Amino-5-fluoro-phenylamino)-hexahydropentalen-2-one, mono-ethylene ketal;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-{4-[5xe2x80x2-(6-fluoro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-octahydro-pentalen-2xe2x80x2-yl]-piperazin-1-yl}-benzonitrile, dimesylate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-{4-[5xe2x80x2-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-octahydro-pentalen-2xe2x80x2-yl]-piperazin-1-yl}-benzonitrile, mesylate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-1-{5xe2x80x2-[4-(5-Fluoro-pyrimidin-2-yl)-piperazin-1-yl]-octahydro-pentalen-2xe2x80x2-yl}-1,3-dihydro-benzoimidazol-2-one, mesylate;
(2xcex1,3axcex2,5xcex1,6axcex2)-5-(6-Fluoro-2-methyl-benzoimidazol-1-yl)-hexahydro-pentalen-2-one;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-{4-[5xe2x80x2-(6-fluoro-2-methylbenzoimidazol-1-yl)-octahydro-pentalen-2xe2x80x2-yl]-piperazin-1-yl}-benzonitrile, dimesylate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-6-Fluoro-2-methyl-1-[5xe2x80x2-(4-phenyl-piperazin-1-yl)-octahydro-pentalen-2xe2x80x2-yl]-1H-benzoimidazole, dimaleate;
(2xcex1,3axcex2,6axcex2)-5-(1H-Indol-3-yl)-3,3a,4,6a-tetrahydro-1H-pentalen-2-one, mono-ethylene ketal;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Fluoro-4-{4-[5xe2x80x2-(1H-indol-3-yl)-octahydro-pentalen-2xe2x80x2-yl]-piperazin-1-yl}-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-3-[5xe2x80x2-(4-Phenyl-piperazin-1-yl)-octahydro-pentalen-2xe2x80x2-yl]-1H-indole, maleate;
(2xcex1,3axcex2,6axcex2)-5-(4-Fluoro-phenoxy)-hexahydro-pentalen-2-one;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex2,6xe2x80x2axcex2)-1-[5xe2x80x2-(4-Fluoro-phenoxy)-octahydro-pentalen-2xe2x80x2-yl]-4-phenyl-piperazine, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex2,6xe2x80x2axcex2)-2-Fluoro-4-{4-[5xe2x80x2-(4-fluoro-phenoxy)-octahydro-pentalen-2xe2x80x2-yl]-piperazin-1-yl}-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex2,6xe2x80x2axcex2)-5-Fluoro-2-{4-[5xe2x80x2-(4-fluoro-phenoxy)-octahydro-pentalen-2xe2x80x2-yl]-piperazin-1-yl}-pyrimidine, maleate;
(2xe2x80x2xcex2,3xe2x80x2axcex2,5xe2x80x2xcex2,6xe2x80x2axcex2)-1-[5xe2x80x2-(4-Fluoro-phenoxy)-octahydro-pentalen-2xe2x80x2-yl]-4-phenyl-piperazine, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex2,6xe2x80x2axcex2)-2-[5xe2x80x2-(4-Phenyl-piperazin-1-yl)-octahydro-pentalen-2xe2x80x2-yl]-isoindole-1,3-dione maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-5-Hydroxy-hexahydro-pentalen-2-one, ethylene ketal;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-Oxo-3-(5-oxo-octahydro-pentalen-2-yl)-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester, ethylene ketal;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-(5-oxo-octahydro-pentalen-2-yloxy)-3H-benzoimidazole-1-carboxylic acid tert-butyl ester, ethylene ketal;
(2xe2x80x2xcex2,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-3-{5xe2x80x2-[4-(4-Fluoro-phenyl)-piperazin-1-yl] octahydro-pentalen-2xe2x80x2-yl}-2-oxo-2, 3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester;
(2xe2x80x2xcex2,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-1-{5xe2x80x2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2xe2x80x2-yl}-1,3-dihydro-benzoimidazol-2-one, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex2,6xe2x80x2axcex2)-2-Fluoro-4-{4-[5xe2x80x2-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-octahydro-pentalen-2xe2x80x2-yl]-piperazin-1-yl}-benzonitrile, maleate;
(2xe2x80x2xcex2,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-1-{5xe2x80x2-[4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2xe2x80x2-yl}-1,3-dihydro-benzoimidazol-2-one, maleate;
(2xe2x80x2xcex2,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-[5xe2x80x2-(4-Phenyl-piperazin-1-yl)-octahydro-pentalen-2xe2x80x2-yloxy]-1H-benzoimidazole, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-(5-Oxo-octahydro-pentalen-2-yl)-isoindole-1,3-dione;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex2,6xe2x80x2axcex2)-2-[5xe2x80x2-(4-Phenyl-piperazin-1-yl)-octahydro-pentalen-2xe2x80x2-yl]-isoindole-1,3-dione, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex2,6xe2x80x2axcex2)-4-{4-[5xe2x80x2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-octahydro-pentalen-2xe2x80x2-yl]-piperazin-1-yl}-2-fluoro-benzonitrile, maleate;
(2xe2x80x2xcex1,3xe2x80x2axcex2,5xe2x80x2xcex2,6xe2x80x2axcex2)-2-{5xe2x80x2-[4-(5-Fluoro-pyrimidin-2-yl)-piperazin-1-yl]-octahydro-pentalen-2xe2x80x2-yl}-isoindole-1,3-dione, maleate;
(2xe2x80x2xcex2,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-{5xe2x80x2-[4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2xe2x80x2-yl}-isoindole-1,3-dione, maleate;
(2xe2x80x2xcex2,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-2-{5xe2x80x2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2xe2x80x2-yl}-isoindole-1,3-dione, maleate; and,
(2xe2x80x2xcex2,3xe2x80x2axcex2,5xe2x80x2xcex1,6xe2x80x2axcex2)-N-[5-(4-Phenyl-piperazin-1-yl)-octahydro-pentalen-2-yl]-benzamide, maleate.
The compounds of formula 1 above may contain chiral centers and therefore may exist in different enantiomeric forms. This invention relates to all optical isomers and all other stereoisomers of compounds of the formula 1 and mixtures thereof, including recemic mixtures of such optical isomers.
This invention also relates to a pharmaceutical composition for treating a condition selected from psychosis, affective psychosis, nonorganic psychosis, personality disorders, schizophrenic and schizoaffective disorders, bipolar disorders, dysphoric mania, Parkinson""s disease, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, nausea, emesis, hyperdermia and amenorrhea in a mammal, including a human, comprising an amount of a compound of the formula 1, or a pharmaceutically acceptable salt or solvate thereof, that is effective in treating such condition, and a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating a condition selected from psychosis, affective psychosis, nonorganic psychosis, personality disorders, schizophrenic and schizoaffective disorders, bipolar disorders, dysphoric mania, Parkinson""s disease, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, nausea, emesis, hyperdermia and amenorrhea in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula 1, or a pharmaceutically acceptable salt or solvate thereof, that is effective in treating such condition.
The present invention also relates to a pharmaceutical composition for treating a condition selected from psychosis, affective psychosis, nonorganic psychosis, personality disorders, schizophrenic and schizoaffective disorders, bipolar disorders, dysphoric mania, Parkinson""s disease, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, nausea, emesis, hyperdermia and amenorrhea in a mammal, including a human, comprising a dopaminergic effective amount of a compound of the formula 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating a condition selected from psychosis, affective psychosis, nonorganic psychosis, personality disorders, schizophrenic and schizoaffective disorders, bipolar disorders, dysphoric mania, Parkinson""s disease, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, and nausea, emesis, hyperdermia and amenorrhea in a mammal, including a human, comprising an administering to said mammal a dopaminergic effective amount of a compound of the formula 1, or pharmaceutically acceptable salt or solvate thereof.
This invention also relates to a pharmaceutical composition for treating a disease or condition, the treatment of which can be effected or facilitated by altering (i.e., increasing or decreasing) dopamine mediated neurotransmission in a mammal, including a human, comprising a dopaminergic effective amount of a compound of the formula 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
This invention also relates to a method of treating a disease or condition, the treatment of which can be effected or facilitated by altering (i.e., increasing or decreasing) dopamine mediated neurotransmission in a mammal, including a human, comprising administering to said mammal a dopaminergic effective amount of a compound of the formula 1, or a pharmaceutically acceptable salt or solvate thereof.
The present invention also relates to a pharmaceutical composition for treating a condition selected from psychosis, affective psychosis, nonorganic psychosis, personality disorders, schizophrenic and schizoaffective disorders, bipolar disorders, dysphoric mania, Parkinson""s disease, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, nausea, emesis, hyperdermia and amenorrhea in a mammal, including a human, comprising a D4 receptor binding effective amount of a compound of the formula 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating a condition selected from psychosis, affective psychosis, nonorganic psychosis, personality disorders, dysphoric mania, schizophrenic and schizoaffective disorders, bipolar disorders, Parkinson""s disease, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, and nausea, emesis, hyperdermia and amenorrhea in a mammal, including a human, comprising an administering to said mammal a D4 receptor binding effective amount of a compound of the formula 1, or pharmaceutically acceptable salt or solvate thereof.
This invention also relates to a pharmaceutical composition for treating a disease or condition, the treatment of which can be effected or facilitated by altering dopamine mediated neurotransmission in a mammal, including a human, comprising a D4 receptor binding effective amount of a compound of the formula 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
This invention also relates to a method of treating a disease or condition, the treatment of which can be effected or facilitated by altering dopamine mediated neurotransmission in a mammal, including a human, comprising administering to said mammal a D4 receptor binding effective amount of a compound of the formula 1, or a pharmaceutically acceptable salt or solvate thereof.
The term xe2x80x9cdopaminergic effective amountxe2x80x9d, as used herein, refers to an amount of a compound sufficient to inhibit the binding of dopamine to a dopamine receptor with the effect of altering (i.e., increasing or decreasing) dopamine mediated neurotransmission.
The term xe2x80x9chaloxe2x80x9d, as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties. Said alkyl group may include one or two double or triple bonds. It is understood that for said alkyl group to include a carbonxe2x80x94carbon double or triple bond at least two carbon atoms are required in said alkyl group. It is also understood that for said alkyl group to include cyclic moieties at least three carbons are required in said alkyl group.
The term xe2x80x9ctreatingxe2x80x9d, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term xe2x80x9ctreatmentxe2x80x9d, as used herein, refers to the act of treating, as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
The term xe2x80x9c4-10 membered heterocyclicxe2x80x9d, as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4-10 atoms in its ring system. Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or more oxo moieties. An example of a 4 membered heterocyclic group is azetedinyl (derived from azetidine). An example of a 5 membered heterocyclic group is thiazolyl and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from the compounds listed above, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
The phrase xe2x80x9cpharmaceutically acceptable salt(s)xe2x80x9d, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the present invention. The compounds of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)] salts. The compounds of the present invention that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
Those compounds of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the calcium, magnesium, sodium and potassium salts of the compounds of the present invention.
The present invention includes the compounds of the present invention, and the pharmaceutically acceptable salts thereof, wherein one or more hydrogen, carbon or other atoms are replaced by isotopes thereof. Such compounds may be useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays.
Compounds of the formula 1 and their pharmaceutically acceptable salts and solvates may be prepared as described below. 
Schemes 1-3 illustrate methods of synthesizing compounds of the formula 1.
With reference to Scheme 1, compounds of formula 1 may be prepared by reacting a compound of the formula 2 or 12 with a compound of the formula 3, wherein substituents X1-X3 and R1-R4 are as defined above. If a compound of formula 2 is used the reaction is generally carried out in an inert solvent at a temperature from about 0xc2x0 C. to about 150xc2x0 C., preferably from about 0xc2x0 C. to about the reflux temperature of the solvent. Suitable solvents include water, cyclic and acyclic mono and dialkylamides (eg, N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidinone (NMP), formamide and acetamide), (C1-C4)alkanols, halogenated hydrocarbon solvents (es, methylene chloride, chloroform and dichloroethane), acyclic and cyclic alkyl ethers (eg, diisopropyl ether and tetrahydrofuran (THF)) and mixtures of two or more of the foregoing solvents. If a compound of the formula 12 is used, the compound of formula 12 is first treated with an aryl or (C1-C4)alkyl-sulfonylchloride in an inert solvent, such as a solvent selected from halogenated hydrocarbon solvents (eg, methylene chloride, chloroform and dichloroethane), acyclic and cyclic alkyl ethers (e., diisopropyl ether and tetrahydrofuran (THF)) and mixtures of two or more of the foregoing solvents, in the presence of a base, such as potassium carbonate or triisopropylamine, followed by treatment with the compound of formula 3 in a solvent comprising a cyclic or acyclic alkyl ether or a (C1-C4)alkanol, or a combination thereof, at a temperature ranging from about 0xc2x0 C. to about the reflux temperature of the solvent in the presence of an acid acceptor such as an alkali carbonate or a tertiary amine to provide a compound of formula 1.
Compounds of the formula 2 may be prepared by reacting a commercially available bicyclooctanone derivative with ethylene glycol, thereby forming a monoacetal, followed by treatment with a compound of the formula R3-Metal wherein Metal is lithium, potassium, sodium or magnesium, preferably lithium, and R3 is as defined above in a solvent such as (C1-C4)alkanols, acyclic and cyclic alkyl ethers, and mixtures of the foregoing solvents, at a temperature of about xe2x88x9280xc2x0 C. to about the reflux temperatue of the mixture, preferably about xe2x88x9280xc2x0 C. to about 0xc2x0 C. The compound of formula R3-Metal may be prepared from the corresponding compound of formula R3-halo, wherein halo is chloro, bromo, or iodo, using conventional organometallic synthetic techniques. The intermediate of formula 6 below is formed following the foregoing procedure 
and this intermediate may be converted into a compound of formula 2 by treating the above intermediate with an acid, such as hydrochloric acid, and optionally followed by catalytic hydrogenation.
Compounds of the formula 12 may be prepared by reducing a compound of formula 2 by, for example, treating a compound of the formula 2 with a hydride reducing agent in an inert solvent at a temperature from about 0xc2x0 C. to about 150xc2x0 C., preferably from about 0xc2x0 C. to about the reflux temperature of the solvent. Suitable solvents include water, cyclic and acyclic mono and dialkylamides, (Cl-C4)alkanols, halogenated hydrocarbon solvents, acyclic and cyclic alkyl ethers, and mixtures of two or more of the foregoing solvents. Compounds of formula 3 wherein X3 is xe2x80x94CH(R5)N(R8)CH(R6)xe2x80x94 are either commercially available or may be prepared by reacting known piperazine derivatives with an alkyl, aryl or heterocyclic group transferring reagent according to methods known to those skilled in the art.
Compounds of formula 3 wherein X3 is xe2x80x94C(R5)xe2x95x90C(R8)CH(R6)xe2x80x94 or xe2x80x94CH(R5)C(R8)xe2x95x90C(R6)xe2x80x94 may be prepared by reacting available or known piperidin-4-one derivatives with an alkyl, aryl or heterocyclic group transferring reagent and then reacting optional intermediates using dehydration or conventional dehydrogenation methods. Compounds of formula 3 wherein X3 is xe2x80x94CH(R5)C(R8)(R9)CH(R6)xe2x80x94 may be prepared by hydrogenating 4-R9-pyridyl derivatives. The foregoing reactions may be carried in an inert solvent selected from cyclic and acyclic mono and dialkylamides, cyclic and acyclic alkyl ketones, (C1-C4)alkanols, acetonitrile, cyclic and acyclic mono and dialkylamides, and mixtures of two or more such solvents, at a temperature ranging from about xe2x88x9225xc2x0 C. to the reflux temperature of the solvent. When protecting groups such as, for example, acetals are used, it may be convenient to remove such groups under acidic procedures. Similarly, other commonly used protecting groups may be introduced and removed using methods generally known to those skilled in the art.
With reference to Scheme 2, compounds of formula 1 may be prepared by reacting a compound of the formula 4 with a compound of formula R3-Metal (wherein xe2x80x9cMetalxe2x80x9d is lithium, potassium, sodium or magnesium), wherein substituents X1-X3 and R1-R3 are as defined above, in a solvent such as (C1-C4)alkanols, acyclic and cyclic alkyl ethers, and mixtures of the foregoing solvents at a temperature of about xe2x88x9280xc2x0 C. to about the reflux temperatue of the mixture, preferably about xe2x88x9280xc2x0 C. to about 0xc2x0 C., to form an intermediate compound of formula 5. The intermediate of formula 5 may be treated with an acid, such as hydrochloric acid, to provide a compound of formula 1. In this method, if both X1 and X2 are xe2x80x94(CH2)jxe2x80x94, then a racemate iof the invention (comprising compounds of formula 1) is formed. The isomers in such racemate can optionally be separated using known techniques, such as, for example, chiral HPLC. In another aspect, the racemate can optionally be treated with hydrogen in the presence of a catalyst to form a further compound of the invention of formula 1, wherein no dased line is indicative of a double bond. If only one of X1 and X2 is O, then the method described in this paragraph results in a compound of formula 1 wherein a dased line represents a double bond. Such compound can likewise optionally be converted to a further compound of the invention of formula 1 (comprising no double bond connecting xe2x80x94(CH2)jxe2x80x94) by treatment with hydrogen in the presence of a catalyst.
The above compound of formula 4 may be prepared by hydrolyzing a compound of the formula 7 below (wherein R1, R2 and X1-X3 are as defined above) 
with an aqueous mineral acid in a solvent selected from cyclic and acyclic mono and dialkylamides, cyclic and acyclic mono and dialkylethers, cyclic and acyclic alkylketones, (C1-C4) alkanols and mixtures of two or more such solvents at a temperature ranging from about xe2x88x920xc2x0 C. to about 150xc2x0 C., preferable at the reflux temperature of the mixture. The above compound of formula 7 may be prepared by treating a compound of formula 3, as described above, with a commercially available or known bicyclooctanone derivative in a solvent selected from cyclic and acyclic mono and dialkylamides, cyclic and acyclic mono and dialkylethers, halogenated hydrocarbons, (C1-C4) alkanols and mixtures of two or more such solvents at a temperature ranging from about 0xc2x0 C. to about 150xc2x0 C., preferable at the reflux temperature of the mixture.
Scheme 3 illustrates an alternative method of preparing a compound of formula 1. In this method, a tin compound of formula 8, wherein R is C1-C4 alkyl and R1, R2, X1 and X2 are as defined above, may be reacted with a derivative of the formula R3-L, wherein R3 is as defined above and L is a leaving group such as bromo or xe2x80x94OSO2CF3, in a solvent, such as benzene or N,Nxe2x80x2-dimethylformamide (DMF), at ambient temperature in the presence of a palladium catalyst to form an intermediate compound of formula 11. The intermediate of formula 11 may be treated with catalytic hydrogenation to provide a compound of formula 1 wherein R1-R3 and X1-X3 are as defined above and R4 is H.
The compound of formula 8, used as a starting material in Scheme 3 above, may be prepared by converting a compound of the formula 9 below 
into a compound of the formula 10 below 
by adding to a solution of the above compound of formula 9 in an anhydrous inert solvent, such as THF, a freshly prepared solution of an Li salt of a secondary amine at low temperature, preferably about xe2x88x9278xc2x0 C., and by reacting the mixture with N-phenyltrifluoromethanesulfonimide. The compound of formula 10 may then be treated with a tin compound of the formula (R)3xe2x80x94Snxe2x80x94Snxe2x80x94(R)3, wherein R is C1-C4 alkyl, in the presence of a palladium catalyst to provide the above starting material of formula 8.
The preparation of other compounds of the formula 1 not specifically described in the foregoing discussion section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.
In each of the reactions discussed or illustrated in schemes 1 to 3 above, pressure is not critical unless otherwise indicated. Pressures from about 0.5 atmospheres to about 4 atmospheres are generally acceptable, and ambient pressure, i.e., about 1 atmosphere, is preferred as a matter of convenience.
Optical isomers of compounds of formula 1, wherein X1 and X2 are both xe2x80x94(CH2)jxe2x80x94 and wherein one dased line represents a double bond can be separated from a racemic mixture using techniques known to those of ordinary skill in the art, such as chiral HPLC. The present invention includes both racemates of such isomers, as well as the isolated isomers themselves.
The compounds of the formula 1 that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula 1 from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
The novel compounds of the formula 1 and their pharmaceutically acceptable salts and solvates (hereinafter xe2x80x9cthe therapeutic compounds of this inventionxe2x80x9d) are useful as dopaminergic agents, i.e., they possess the ability to alter dopamine mediated neurotransmission in mammals, including humans. They are therefore able to function as therapeutic agents in the treatment of a variety of conditions in mammals, the treatment or prevention of which can be effected or facilitated by an increase or decrease in dopamine mediated neurotransmission. Such conditions include psychosis, affective psychosis, nonorganic psychosis, personality disorders, schizophrenic and schizo-affective disorders, bipolar disorders, dysphoric mania, emesis, nausea, Parkinson""s disease, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, hyperdermia and amenorrhea.
The therapeutic compounds of this invention can be administered orally, transdermally (es through the use of a patch), rectally, parenterally or topically. Oral administration is preferred. In general, these compounds are most desirably administered in dosages ranging from about 0.01 mg up to about 250 mg per day, although variations may occur depending on the weight and condition of the person being treated and the particular route of administration chosen. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
The therapeutic compounds of this invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the two routes previously indicated, and such administration may be carried out in single or multiple doses. More particularly, the therapeutic compounds of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
The D4 dopaminergic activity of the compounds of the present invention may be determined by the following procedures A and B.
Procedure A
The determination of D4 dopaminergic activity has been described by Van Tol et al., Nature, vol. 350, 610 (London, 1991). Clonal cell lines expressing the human dopamine D4 receptor are harvested and homogenized (teflon pestle) in a 50 mM Tris.HCl (pH 7.4 at 4xc2x0 C.) buffer containing 5 mM EDTA, 1.5 mM calcium chloride (CaCl2), 5 mM magnesium chloride (MgCl2), 5 mM potassium chloride (KCl) and 120 mM sodium chloride (NaCl). The homogenates are centrifugated for 15 min. at 39,000 g, and the resulting pellets resuspended in a buffer at a concentration of 150-250 mg/ml. For saturation experiments, 0.25 ml aliquots of tissue homogenate are incubated in duplicate with increasing concentrations of [3H] Spiperone (70.3 Ci/mmol; 10-3000 pM final concentration) for 30-120 minutes at 22xc2x0 C. in a total volume of 1 ml. For competition binding experiments, assays are initiated by the addition of 0.25 ml of membrane and incubated in duplicate with the indicated concentrations of competing ligands (10xe2x88x9214-10xe2x88x9213 M) and [3H]Spiperone (100-300 pM) in either the absence or presence of 200 uM GPP(NH)p (5xe2x80x2/guanylylimidodiphosphate), where indicated, for 60-120 minutes at 22xc2x0 C. Assays are terminated by rapid filtration through a Titertek cell harvester and the filters subsequently monitored for tritium as described by Sunahara, R. K. et al., Nature, 346, 76-80 (1990). For all experiments, specific [3H]Spiperone binding is defined as that inhibited by 1-10 mM (+) Butaclamole or 1 mM Spiperone. Both saturation and competition binding data are analyzed by the non-linear least square curve-fitting program Ligand run on a digital Micro-PP-11 as described by Sunahara et. al.
Procedure B
Chinese hamster ovary (CHO) cells expressing the human D4 dopamine receptor are grown to confluence in Minimal Essential Alpha Media (manufactured by Gibco) supplemented with 2.5% Fetal Bovine Serum (not heat inactivated), 2.5% Equine Serum (heat inactivated), and 500 xcexcg/ml Geneticin. Monolayers are disrupted and cells dislodged with 5 mM ethylenediaminetetraacetic acid (EDTA) and resuspended in phospate buffered saline buffer containing 5 mM MgCl2, 30 mM hydroxyethylpiperazine-N-ethanesulfonic acid (HEPES), 300 xcexcM 3-isobutyl-1-methyl-xanthine (IBMX, a phosphodiesterase inhibitor), and 5.6 mM dextrose. Cells are exposed to 5 xcexcM forskolin (an adenylate cyclase activator), forskolin plus test compounds or quinpirole (a D4 receptor agonist), or forskolin plus quinpirole plus antagonist for 11 minutes. In experiments with antagonists, cells may be exposed to antagonists for 11 minutes piror to agonist challenge. The effect of test compounds in the absence of the agonist quinpirole is used to judge agonist activity. D4 agonists produce an inhibition of cAMP accumulation which can be reversed by D4 receptor antagonists. The reaction is terminated with addition of 6N perchloric acid, and samples neutralized with 5N potassium hydroxide and 2M Tris buffer. Cyclic AMP levels are measured using a commercially available competitive binding kit. IC50 vlaues are calculated by linear regression analysis of the concentration-response curves. Ki values are calculated using the equation: Ki=IC50/(1+[agonist]/[agonist EC50]) (see Minneman, K. P. and Johnson, R. D., J. Pharmacol. Exp. Ther., 230(2), 317-323 (1984)).